Abstract 3864: A novel PDE10/β-catenin pathway inhibitor, MCI-030, for the treatment of colorectal cancer

Abstract

Abstract Over 90% of colorectal cancers harbor mutations in β-catenin or pathway components (e.g. APC) that stabilize β-catenin, causing nuclear translocation and constitutive Tcf-mediated transcription of genes encoding proteins essential for the proliferation and survival of tumor cells. We recently reported that the cyclic nucleotide degrading phosphodiesterase (PDE) isozyme PDE10 is overexpressed in colorectal cancers relative to normal tissue. Its expression and enzymatic activity are essential for colon tumor cell growth, as evidenced by knockdown of PDE10 expression using siRNA or inhibition of enzyme activity using known inhibitors such as PF-2545920. PDE10 inhibition in tumor cells expressing high levels of PDE10 causes increased intracellular cGMP levels to activate PKG and phosphorylate β-catenin, which induces ubiquitination and proteasomal degradation to suppress nuclear translocation and Tcf transcriptional activity. Conversely, ectopic expression of PDE10 in normal colonocytes or precancerous adenoma cells causes increased levels of β-catenin and the expression of proteins (e.g. cyclin D and survivin) essential for the proliferation and survival of tumor cells. To identify novel antitumor PDE10 inhibitors, we screened a chemically diverse library of indenes for PDE10 and tumor cell growth inhibitory activity. Following extensive chemical optimization, MCI-030 emerged as a potent and selective inhibitor of tumor cell growth. Similar to PF-2545920, but with appreciably greater potency and tumor cell selectivity, MCI-030 inhibited colon tumor cell growth by activating cGMP/PKG signaling to phosphorylate and induce β-catenin degradation. MCI-030 also inhibited colon tumor cell spheroid formation and reduced spheroid size and growth at concentrations that inhibit PDE10. Oral administration of MCI-030 significantly inhibited colon tumor formation in the Apc+/min-FCCC mouse model without discernable toxicity. Importantly, unlike PDE10 inhibitors developed to cross the blood-brain barrier for the treatment of CNS disorders, MCI-030 lacks the sedation side effects. Together, these findings support preclinical development of MCI-030 for the treatment of colorectal cancer as a novel PDE10 inhibitor capable of selectively inhibiting the growth of tumors harboring β-catenin or APC mutations. Funding provided by NCI grants R01CA131378, R01CA148817, R01CA197147, and R01CA155638. Citation Format: Antonio B. Ward, Xi Chen, Jacob Valiyaveettil, Kevin Lee, Wen-Chi L. Chang, Yulia Maxuitenko, Veronica Ramirez-Alcantara, Kristy Berry, Luciana Madeira da Silva, Bing Zhu, Tyler Mattox, Michael R. Boyd, Adam B. Keeton, Margie L. Clapper, Harry S. Cooper, Gary A. Piazza. A novel PDE10/β-catenin pathway inhibitor, MCI-030, for the treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3864.